Cardiotrophin-1 aktiviert humane periphere mononukleäre Zellen und induziert die Synthese von Tumornekrosefaktor-alpha

Wang, Zhenhua

Plasma cardiotrophin-1 (CT-1) levels increase with the severity of congestive heart failure (CHF). The purpose of this study is to elucidate the role of CT-1 on the activation of peripheral blood mononuclear cells (PBMC) and further evaluate its effects on the expression of TNF-α in them. PBMC were isolated from human whole blood, and cultured in vitro. Intracellular signaling proteins were determined by Western blotting. Nuclear translocation of transcription factors was evaluated by electrophoretic mobility shift assay. mRNA and protein levels of cytokines were measured by real-time PCR, ELISA and flow cytometry. This study showed that both subunits of gp130/LIFR-β heterodimer receptor for CT-1 action were expressed on PBMC. Via this receptor, CT-1 activated PBMC by evoking extracellular-signal-regulated kinase (ERK) and P38 mitogen-activated protein kinase (MAKP) signaling pathways, and promoting TNF-α expression. CT-1 significantly induced TNF-α production at both mRNA and protein levels in PBMC. The subpopulation of monocytes but not lymphocytes was responsible for this effect. In addition, CT-1 can induce nuclear factor kappa B (NFκB) translocation into the nucleus in PBMC, which was mediated by inhibitor of kappa B (IκB) degradation. The NFκB inhibitor parthenolide interrupted nuclear translocation of NFκB and completely inhibited the CT-1-induced TNF-α expression in PBMC, whereas neither the P38 MAPK inhibitor SB203580 nor the ERK inhibitor PD98059 had any effects on them. These results indicate that NFκB nuclear translocation is essential for CT-1-induced TNF-α expression in PBMC and that CT-1 might activate NFkB via Raf-1 directly as ‘‘skip’’ activation sequences but not via Raf-1/MEK/MAPKs pathway. This study may offer a new mechanism of immune activation in CHF, and also elucidate a potential role of CT-1 in the pathophysiology of CHF. Modulating CT-1 may be an interesting pharmacological target in the treatment of CHF.

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Wang, Zhenhua: Cardiotrophin-1 aktiviert humane periphere mononukleäre Zellen und induziert die Synthese von Tumornekrosefaktor-alpha. 2012.

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